Study on rapid diagnosis and B cell defect of X-linked agammaglobulinemia

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X-linked agammaglobulinemia (XLA), a relatively common immunodeficieny disorder, is characterized by the paucity of peripheral blood B cells, markedly reduced levels of serum immunoglobulins, and the occurrence of severe bacterial infection during the early period of infancy. In 1993, the causative gene for XLA has been identified as Bruton's tyrosine kinase (Btk), which plays a pivotal role in B cell activation and early B cell differentiation. The detection of XLA patients and carriers has been performed by demonstration of Btk mutations internationally. In the present study, we developed the clinically useful and simple method for identification of XLA and its carrier, searched for the distribution of XLA in Japan by the combined use with Btk genetic analysis, and elucidated clinical variability of XLA. In addition, we attempted to learn some of the pathogenic significance of Btk in XLA. The results obtained here are as follows :1) Employing Btk expression in monocytes, we showed th … More at a flow cytometric analysis using anti-Btk monoclonal antibody could detect easily and rapidly XLA and its carrier.2) By the use of both flow cytometric and genetic analyses, we newly identified 65 cases with XLA, resulting in our confirmation of totally 100 families with XLA in Japan.3) Atypical cases with XLA, who showed the normal range of serum IgG or the adult onset, were discovered.4) Investigation of Japanese Immunodeficiency Registry presented the possibility that a number of XLA cases without family history often misdiagnosed as CVID.5) Examination of bone marrow from XLA using anti-VpreB monoclonal antibody for the first time demonstrated that the genetic defect in XLA might impede the maturational evolution of pro-B cells into the later stage of pre-B cells in B cell differentiation pathway.6) It was demonstrated that neutropenia was occasionally associated with XLA, and Btk was possibly involved for the essential function of monocytes/macrophages in neutropoiesis through production of some cytokines. Less